Vaccination

Last updated May 25, 2011

Note: This document is best viewed with Internet Explorer for both format and function.

Current Anthrax Vaccine
Vaccine Efficacy
Recommendations for Use
Dosage, Route of Administration, and Vaccination Schedule
Contraindications and Precautions
Adverse Reactions
Postlicensure Adverse Event Reporting
Development of New Vaccines
Bibliography

Current Anthrax Vaccine

AVA (BioThrax), manufactured by BioPort, a subsidiary of Emergent BioSolutions, Inc in Lansing, Michigan, is the only licensed human anthrax vaccine in the United States (Emergent BioSolutions: BioThrax package insert).
Most AVA vaccine has been used by the US military; it is not available to the general public (except through public health officials during an anthrax emergency as part of the Strategic National Stockpile).
AVA is prepared from cell-free filtrates of microaerophilic cultures of an avirulent, nonencapsulated strain of B anthracis. The final product contains no live or dead bacteria.
The final product is formulated to contain 1.2 mg/mL aluminum, added as aluminum hydroxide in 0.85% sodium chloride.
The final product is formulated to contain 25 mcg/mL benzethonium chloride and 100 mcg/mL formaldehyde, added as preservatives.

Vaccine Efficacy

Randomized controlled trials on the clinical effectiveness, immunogenicity, and safety of anthrax vaccines were recently reviewed. The authors concluded that vaccines based on anthrax antigens are immunogenic in most vaccinees with few adverse events, although limited data were available (Donegan 2009).

The efficacy of AVA is based on several animal studies, one controlled human trial, and immunogenicity data from humans and other mammals (Brachman 1962, Gladstone 1946, Mahlandt 1966, Turnbull 1986). One study demonstrated that vaccination of adults induced an immune response in 83% of vaccinees 2 weeks after the first dose and in 91% of vaccinees who received two or more doses (Turnbull 1986). Approximately 95% of vaccinees seroconverted after three doses. However, the correlation between antibody titer and protection against infection has not been defined.
Analysis of serum from vaccinees and clinical anthrax patients shows that vaccination with three AVA injections and anthrax infection both elicited anti-PA, IgG1, IgG2, and IgG3 subclass responses (Semenova 2007). One study suggests that AVA-induced antibodies to PA are sufficient to neutralize toxin activity and that AVA-induced LF and EF antibodies do not contribute to anthrax toxin neutralization in humans (Taft 2008).
Duration of efficacy is unknown, although data from animal studies suggest that it may be 1 to 2 years after two doses. Studies of military personnel vaccinated during the 1990-1991 Gulf War indicate that antigen-specific T-cell recall responses present in the circulation are comparable in magnitude to those of tetanus-diphtheria toxoids (Allen 2006).
Anthrax vaccines intended for animals should not be used in humans.

Recommendations for Use

Preexposure Vaccination

Preexposure immunization with AVA is licensed for individuals aged 18 to 65 who have a high likelihood of coming into contact with B anthracis (CDC 2010: Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP], 2009). The vaccine is not licensed for pregnant women. The vaccine also is not licensed for children because no studies have been conducted in the pediatric population; however, the vaccine probably is safe and efficacious in children, based on experience with other inactive vaccines (Inglesby 2002).

Preexposure vaccination is indicated for the following groups (CDC 2010: Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP], 2009):

Laboratory personnel engaged in work involving production of quantities or concentrations of B anthracis cultures
Laboratory personnel handling environmental specimens (especially powders) and performing confirmatory testing for B anthracis in LRN reference and national laboratories
Workers who will be making repeated entries into known B anthracis-spore-contaminated areas after a terrorist attack
Persons who come in contact in the workplace with imported animal hides, furs, bone meal, wool, animal hair, or bristles in areas where current standards and restrictions are insufficient to prevent exposure to anthrax spores
Veterinarians and other high-risk persons handling potentially infected animals in areas of the world that have a high incidence of anthrax cases (Note: The incidence of anthrax in the United States is low; therefore, routine vaccination of US veterinarians is not recommended)
Military personnel and other select populations who have a risk for exposure to weaponized B anthracis. After a lapse due to legal action, the DoD has resumed mandatory vaccinations for military personnel, essential DoD civilians, contractors stationed in the Middle East and South Korea, and units involved in homeland bioterrorism defense (DoD 2006, and see Oct 19, 2006, CIDRAP News story).

Laboratory workers using standard BSL-2 practices are not considered by the Advisory Committee on Immunization Practices (ACIP) to be at increased risk for exposure to B anthracis spores.

Postexposure Vaccination

ACIP guidelines state that anthrax vaccine can be used in combination with antibiotics following inhalational exposure to anthrax (CDC 2010: Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP], 2009):

Exposed persons should receive a three-dose regimen of vaccine subcutaneously (0, 2, and 4 weeks following exposure) and at least a 60-day course of antimicrobial therapy. Persons who do not receive vaccine also should take antimicrobial therapy for at least 60 days.
Anthrax vaccine is not currently licensed for postexposure use, so it must be given under an investigational new drug (IND) application with the FDA.

Due to problems of noncompliance and side effects associated with prolonged antibiotic treatment, investigators have studied whether a short course of antibiotics combined with vaccination could provide protection after exposure. Monkeys were exposed to an aerosol dose (1,600 LD₅₀) of B anthracis spores (Vietri 2006). One group of animals received only ciprofloxacin (an initial loading dose of 250 mg of ciprofloxacin within 2 hours after exposure followed by 125 mg twice daily for 14 days). Another group of animals received ciprofloxacin (as described) and was vaccinated (0.5 ml of AVA on day 0 within 2 hours after exposure, and on days 14 and 28). In contrast to the untreated control group, all animals in both the ciprofloxacin-only and the ciprofloxacin-plus-vaccine groups survived during the 14 days of antibiotic prophylaxis. However, once the antibiotics were discontinued, only four of nine animals (44%) in the ciprofloxacin-only group survived compared with 10 of 10 animals (100%) in the ciprofloxacin-plus-vaccine group. These data provide evidence that postexposure vaccination can shorten the duration of antibiotic prophylaxis required to protect against inhalational anthrax.

Dosage, Route of Administration, and Vaccination Schedule

Each vaccine dose is 0.5 mL. The current vaccination schedule consists of a primary series of two intramuscular injections followed by three booster intramuscular injections as outlined in the table below. In December 2008, the FDA approved a change in the primary series from three doses subcutaneously (0, 2, and 4 weeks) to two doses intramuscularly (0 and 4 weeks). The ACIP supported this change in February 2009 (see Feb 25, 2009, CIDRAP News story). The change is based on a randomized, phase 4 trial, which found that a three-dose intramuscular schedule provided similar immunologic priming by month 7 compared with a four-dose subcutaneous regimen. An intramuscular route also significantly reduced the occurrence of injection-site adverse events (Marano 2008).

To maintain immunity among those with anticipated ongoing exposure, the manufacturer recommends an annual booster injection using the same dosage and route after completion of the primary and booster series.

Schedule for Anthrax Vaccination^a
Primary series (2 injections)	Week 0 Week 4
Booster series (3 injections)^b	6 mo after primary series 12 mo after primary series 18 mo after primary series
^aAll doses are 0.5 mL and should be given intramuscularly. ^bAdditional boosters to be given annually (same route and dose) for those at ongoing risk of exposure.

Contraindications and Precautions

The main contraindication is a history of anaphylaxis after receiving a dose of AVA or any of the vaccine components.
History of anthrax disease may increase the potential for severe local adverse reactions.
If AVA is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the immune response may be diminished.
AVA is labeled as Pregnancy Category D (Emergent BioSolutions: BioThrax package insert). According to the manufacturer's package insert, "Pregnant women should not be vaccinated against anthrax unless the potential benefits of vaccination have been determined to outweigh the potential risk to the fetus."
Few studies have been published regarding the use of anthrax vaccine in pregnant women.

A study among US army women demonstrated that anthrax vaccine had no effect on subsequent pregnancies, birth rates, or adverse birth outcomes, although the power to detect adverse birth outcomes in the cohort was limited (Wiesen 2002).
A retrospective cohort study evaluated birth defects in relation to maternal anthrax vaccination for infants born to US military service women from 1998 through 2004. Among 115,169 infants born to military women during this period, 37,140 were born to women ever vaccinated, and 3,465 were born to women vaccinated in the first trimester of pregnancy. Birth defects were slightly more common among infants born to women vaccinated during the first trimester compared with infants born to women vaccinated beyond the first trimester; however, this finding was not statistically significant. An analysis of infants born to women vaccinated in the first trimester and infants born to women who were never vaccinated found that birth defects were slightly higher (odds ratio = 1.2; 95% confidence interval = 1.02 to 1.42) in the vaccinated group (Ryan 2008).

Adverse Reactions

Injection site adverse reactions are the most common and occur in more than half of vaccine recipients. These include warmth, tenderness, itching, erythema, induration, edema, and nodule formation. Most local adverse reactions are mild or moderate in severity.
Systemic reactions (fever, chills, myalgia, nausea) following vaccination may occur in 10% to 25% of recipients.
One report identified five cases of new-onset rheumatoid arthritis (RA) temporally related to anthrax vaccine. The most recent occurred in a 42-year-old man who experienced knee and interphalangeal joint stiffness and pain 5 days after receiving the first dose of anthrax vaccine. Serologic and radiologic examinations revealed mild degenerative changes in his hands and knees bilaterally (Vasudev 2006). It is unclear at this time whether or not these case reports represent a true association between anthrax vaccination and RA, since this issue has not been systematically evaluated.

Postlicensure Adverse Event Reporting

Between 1998 and 2008, the Vaccine Adverse Event Reporting System (VAERS) received 6,015 reports of adverse events following anthrax vaccination (CDC 2010: Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices[ACIP], 2009). The most frequent adverse events that occurred were arthralgia (n = 1,036, 17%), headache (981, 16%), pruritus (878, 15%), pain (824, 14%), injection-site erythema (753, 13%), fever (655, 11%), erythema (626, 10%), injection-site pain (613, 10%), rash (606, 10%), and myalgia (583, 10%). A total of 600 (10%) serious adverse events were reported.
Review of anthrax vaccination data from a 1967 to 1972 study and medical literature from 1955 to 2005 suggests that women have at least twice the risk of having a vaccine reaction compared with men. The age-adjusted relative risk for injection site reaction was 2.78 (95% confidence interval, 2.29 to 3.38) (McNeil 2007: Short-term reactogenicity and gender effect of anthrax vaccine: analysis of a 1967-1972 study and review of the 1955-2005 medical literature).
Between December 15, 1997, and April 12, 2000, 425,976 service members received 1,620,793 doses of AVA. As of April 7, 2000, 428 VAERS reports had been received through the DoD (CDC 2000: Surveillance for adverse events associated with anthrax vaccine—US Department of Defense, 1998-2000). Of these reports, 311 (72.7%) involved systemic reactions, 78 (18.2%) were mild or moderate local reactions, and 39 (9.1%) were large or complicated local reactions. As of March 21, 2000, a panel of civilian scientific and medical experts had not identified any pattern of adverse events among 674 reports that had been reviewed. Comparative analysis of immunization records in the military VAERS reports and the Defense Medical Surveillance System suggests that the information contained in both sets of records is similar for anthrax and for nonanthrax vaccine immunizations (McNeil 2007: A comparative assessment of immunization records in the Defense Medical Surveillance System and the Vaccine Adverse Event Reporting System).
Some reports have suggested an association between optic neuritis and anthrax vaccination (or receipt of other vaccines). However, a matched case-control study among US military personnel from Jan 1, 1998, through Dec 31, 2003, revealed no significant associations between optic neuritis and anthrax vaccination (Payne 2006).

The Institute of Medicine's Committee to Assess the Safety and Efficacy of Anthrax Vaccine found no evidence that people receiving the anthrax vaccine are at increased risk of life-threatening or permanently disabling adverse events. An FDA review of VAERS reports also found no causal relationship between anthrax vaccination deaths and other serious adverse events (other than some serious injection site and allergic reactions). Similarly, the HHS Anthrax Vaccine Expert Committee concluded that there was not a high frequency or an unusual pattern of serious or other medically important adverse events. A recent review of 4,753 anthrax vaccine–related VAERS reports from January 1, 1990 through January 16, 2007 confirmed these previous findings (Niu 2009).

Development of New Vaccines

Research into new anthrax vaccines is ongoing. Most vaccines that have been studied utilize recombinant technology or employ new adjuvants to increase the immune response.

Current human anthrax vaccines consist of supernatant material from cultures of a toxigenic, nonencapsulated strain of B anthracis. Second-generation vaccines using recombinant PA (rPA) are being developed as an alternative, as much of the immunogenicity of the current vaccine arises from this protein component (Rhie 2005).
Emergent BioSolutions (maker of the current anthrax vaccine) is studying a new candidate vaccine (AV7909), which comprises AVA in combination with the immunostimulatory compound CPG 7909 as an adjuvant (Emergent BioSolutions 2008).
One study suggests that oral, live, attenuated, spore-based vaccines could offer long-lasting protection against anthrax in humans (Aloni-Grinstein 2005). The investigators administered a previously described live, attenuated, nontoxinogenic, nonencapsulated B anthracis spore vaccine orally to guinea pigs and found that protective immunity correlated with development of a threshold level of PA neutralizing antibody titers. Protective immunity also appeared to be long-lasting.
Several animal studies have shown that the presence of EF in vaccine preparations can promote protective immunity against anthrax, and inclusion of EF in multicomponent subunit vaccines is a consideration (Quesnel-Hellmann 2006, Zeng 2006).
Combination vaccines such as one against anthrax and plague may represent the next generation of vaccines against potential agents of bioterrorism (DuBois 2007).


Home	Mission & Activities	About Us	Your Support	Contact Us